Developement of an oral form of vinorelbine for pediatric use in the treatment of rhabdomyosarcoma

6 October 2022

J-C. Mabin1 , F-X. Legrand2, L. Denis1, A.Doweki1, 3, M. Annereau 1, 4, A. Rieutord1
1 Clinical Pharmacy Department, Gustave Roussy Cancer Campus, 94800 Villejuif, France
2 Paris-Saclay University, CNRS, Galien Institute Paris-Saclay, 91190, Orsay, France.
3 Paris-Saclay University, Lipids: analytical and biological systems, 91190, Orsay, France.
4 Paris-Saclay University, Matériaux et santé, 91190, Orsay, France.

In pediatrics, vinorelbine is used in the maintenance phase for the treatment of rhabdomyosarcoma. Current oral forms cause mucosal toxicities due to the vesicant property of vinorelbine. They also lead to variability in pharmacokinetics and are not adapted to the whole pediatric population.
The aim of this work is to develop a suitable oral form of vinorelbine that will allow a better control of the pharmacokinetics and will suppress the oropharyngeal toxicities.
We worked on the development of a liquid form, specifically on how to encapsulate vinorelbine in cyclodextrins to avoid oropharyngeal toxicities previously described. Firstly, we developed and validated a stability indicative method to quantify vinorelbine by Ultra High-Pressure Liquid Chromatography coupled with UV detection. Then we studied the interaction of vinorelbine with cyclodextrin using isothermal titration calorimetry (ITC) to screen 12 nontoxic cyclodextrins approved by the FDA and EMA. Two-dimensional NMR spectroscopy of proton were used to caracterize the type of interaction between the compounds.
The local method stability indicative is validate. The ITC method showed an interaction between four cyclodextrins and vinorelbine. 2D NMR confirmed an encapasulation type of interaction of vinorelbine in those four cyclodextrins, and we selected the one showing the highest complexation for a lower amount of cyclodextrin.
To complete this work, further experiments such as calorimetry manipulations, in vitro toxicity studies, organoleptic properties evaluation and animal models are considered in order to validate the definitive formulation and to ensure that it meets our requirements.

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